Full Text PA-97-004
 
MOLECULAR AND GENETIC STUDIES IN PANCREATITIS AND PANCREATIC CANCER
 
NIH GUIDE, Volume 25, Number 36, October 25, 1996
 
PA NUMBER: PA-97-004
 
P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Molecular Genetics 
  Digestive Diseases & Disorders 

 
National Institute of Diabetes and Digestive and Kidney Diseases
National Cancer Institute
 
PURPOSE
 
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the National Cancer Institute (NCI) wish to encourage
experienced and new investigators to pursue basic and clinical
investigations into the molecular genetics of acute and chronic
pancreatitis as well as the "preneoplastic" genetic changes that
occur and predispose individuals to adenocarcinoma of the pancreas.
Basic studies include the generation of transgenic animal models of
pancreatitis that show inherited forms of pancreatitis.
Particularly, organ-specific transgenic mice are sought which exhibit
acute or chronic pancreatitis.  Alternatively, for pancreatic cancer,
the fifth most common cause of death from cancer, basic science
studies are sought which identify the numerous genetic alterations
that are involved in this form of carcinogenesis.  Such studies could
utilize transgenic mice or gene knock-out mice to systematically
determine pancreatic preneoplastic genetic events.
 
Clinical studies are also sought that increase our knowledge in the
early detection and diagnosis, prognostication, prevention and
treatment of pancreatitis and pancreatic cancer.  These studies could
utilize the recent advances in the field which identify a genetic
locus on human chromosome 7 that exhibits linkage to hereditary
pancreatitis as well as the recent observation of allelic loss of
tumor suppressor gene(s) on human chromosome 18 as a early event in
human pancreatic carcinogenesis.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas. This Program
Announcement, Molecular and Genetic studies in Pancreatitis and
Pancreatic Cancer, is related to the priority area of cancer
prevention and control.  Potential applicants may obtain a copy of
"Healthy People 2000 (Full Report:  Stock No. 017-001-00474-0 or
Summary Report: Stock No. 017-001-00473-1) through the Superintendent
of Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Eligible applicants include established or new investigators who have
an interest in pancreatitis, pancreatic cancer or the application of
molecular and/or genetic techniques to laboratory technologies for
the development of new animal models of pancreatitis or pancreatic
cancer.  Applicants are encouraged to develop multidisciplinary
collaborations and develop new hypotheses related to the pathogenesis
of pancreatitis or the early detection and diagnosis,
prognostication, prevention and treatment of pancreatitis and/or
pancreatic cancer.
 
Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) (R29) awards.  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as principal investigators.
 
MECHANISM OF SUPPORT
 
The support for this program announcement will be through the NIH
research project grant (R01) award, the FIRST (R29) award and the
small grants (R03) award.  Initial funding can be for a maximum of
three years using this mechanism.  FIRST (R29) award applicants must
adhere to the R29 Administrative Guidelines (rev. Feb. 94) for
eligibility, budget and period of award.  Potential FIRST (R29) award
applicants should refer to the announcement on "Just-in-Time
Procedures for FIRST and Career Awards" (NIH Guide, Vol. 25, No. 10,
March 29, 1996) for information on recent changes in guidelines for
FIRST award application format.  The small grants research program
(R03) provides limited funds (maximum of $50,000 direct costs per
year) for short term (up to two years) research projects.  These
grants are non-renewable, but continuation of projects developed
under this program can be supported by the investigator-initiated
research project grant (R01) mechanism.  Applicants will be
responsible for the planning, direction, and execution of the
proposed project.
 
The award of grants in response to this PA is also contingent upon
the availability of funds.  Awards will be administered under PHS
grants policy as stated in the PHS Grants Policy Statement (rev.
4/94).
 
RESEARCH OBJECTIVES
 
This Program Announcement calls for basic and clinical research using
molecular and genetic approaches for the elucidation of the molecular
genetics of pancreatitis as well as the preneoplastic genetic changes
that occur which predispose individuals to pancreatitis or
adenocarcinoma of the pancreas.  Basic research could include the
generation of transgenic animal models of pancreatitis which show
inherited forms of pancreatitis.  Particularly, organ-specific
transgenic mice are sought which exhibit acute or chronic
pancreatitis.
 
Alternatively, for pancreatic cancer,the fifth most common cause of
death from cancer, basic science studies are sought which identify
the numerous genetic alterations that are involved in this form of
carcinogenesis.  Such studies could utilize transgenic mice or gene
knock-out mice to systematically determine pancreatic preneoplastic
genetic events which could be applied to the pathogenesis of either
pancreatitis or pancreatic cancer.
 
Clinical investigations are sought which will increase our knowledge
in the early detection and diagnosis, prognostication, prevention and
treatment of pancreatitis and pancreatic cancer.  Research
investigation could focus on the detection of pancreatic cancer at an
early stage or the identification of individuals who may be at high
risk.
In the latter case, cohort studies of patients with chronic
pancreatitis or other chronic conditions associated with an increased
risk of pancreatic cancer, could be conducted to identify individuals
with potentially curable pancreatic cancer, genetic markers or
precursor lesions in this high-risk patient population or for
oncogene expression in the development of pancreatic neoplastic
lesions.  Early detection of established cancer can be based on
genetic tests of blood or metabolic products excreted in the bile,
pancreatic juice, stool or urine.  Tumor-associated antigens, peptide
hormones and mutated oncogenes are also areas of interest.  Factors
directly causing an increased risk of pancreatic cancer could be
identified through:  1) putative carcinogenic products secreted in
the pancreatic juice after absorption from the intestine; 2) the
ability of the pancreas to activate drugs or other chemicals to
carcinogenic or toxic agents that can be detected in the blood, stool
or urine; and 3) genetic testing for the existence of specific
metabolic pathways that may predispose to carcinoma.
 
Other studies could seek to elucidate the clinical sigificance of
genetic linkage of specific human chromosomal loci to hereditary
pancreatitis or the loss of tumor suppressor gene(s) as an early
event in pancreatic carcinogenesis.
 
Results of the research should lead to additional methods for early
detection of pancreatitis or pancreatic cancer (such as genetic
tests) or improve our understanding of pancreatic metabolism
including the synthesis and secretion of specific metabolites.
Alternatively, the possible role of the pancreas in activating (or
deactivating) procarcinogens absorbed from the intestine or whether
genetically determined metabolic pathways that may activate
procarcinogens vary in different populations could be investigated.
In addition, the elucidation of the development of preneoplastic
lesions of the pancreas to neoplasia is also sought.  Early detection
could include research on possible new tumor markers such as peptide
hormones or glycoproteins.  Patient-based studies should also provide
a better understanding of cancer risk and progression among groups or
populations at increased risk such as middle-age and older African
American men, smokers or patients with pancreatitis as well as
determine why the incidence and mortality of pancreatic cancer is
higher in African Americans than in non-Hispanic whites.
Identification of metabolic pathways associated with cancer may have
advantages for cancer control since individuals who are at high risk
because of pancreatic metabolism may be candidates for dietary
modification or prophylatic chemotherapy.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
 
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
Applicants from institutions which have a General Clinical Research
Center (GCRC) funded by the NIH Center for Research Resources (NCRR)
may wish to identify the GCRC as a resource for conducting the
proposed research.  In such a case, a letter of agreement from either
the GCRC program director or the principal investigator should be
included with the application.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research, or may
be obtained from the Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/435-0714, email: asknih@odrockm1.od.nih.gov.
 
The program announcement title and number must be typed on line 2 of
the face page of the application form and the YES box must be marked.
 
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer review group convened in accordance with NIH peer
review procedures. As part of the initial merit review, all
applications will receive a written critique and undergo a process in
which only those applications deemed to have the highest scientific
merit, generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.
 
Review Criteria
 
o  scientific, technical, or medical significance and originality of
proposed research;
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment.
 
o  availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries which are not readily
available in the United States or which provide augmentation of
existing U.S. resources.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:
 
o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program priority.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Thomas F. Kresina, Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8871
FAX:  (301) 480-8300
Email:  tk13v@nih.gov
 
Dr. Andrew Chiarodo
Organ Systems Coordinating Branch
National Cancer Institute
Executive Plaza North, Room 512
Bethesda, MD  20892
Telephone:  (301) 496-8528
Email:  chiaroda@debdcep1.nci.nih.gov
 
Direct inquiries regarding fiscal and administrative matters to:
 
Ms. Donita Marconi
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8860
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.848 and 93.399.  Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children. This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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